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| Item Type: | Article |
|---|---|
| Title: | Interleukin-12 signaling drives Alzheimer’s disease pathology through disrupting neuronal and oligodendrocyte homeostasis |
| Creators: |
Schneeberger, S., Kim, S.J.  ORCID: https://orcid.org/0000-0001-8357-0073, Geesdorf, M.N., Friebel, E. ORCID: https://orcid.org/0000-0003-1419-2376, Eede, P., Jendrach, M. ORCID: https://orcid.org/0000-0002-8601-2277, Boltengagen, A. ORCID: https://orcid.org/0000-0002-8356-9766, Braeuning, C. ORCID: https://orcid.org/0009-0007-1439-9920, Ruhwedel, T. ORCID: https://orcid.org/0000-0002-9535-9395, Hülsmeier, A.J. ORCID: https://orcid.org/0000-0001-6987-8979, Gimber, N. ORCID: https://orcid.org/0000-0001-9456-3063, Foerster, M., Obst, J., Andreadou, M. ORCID: https://orcid.org/0000-0001-6757-4664, Mundt, S. ORCID: https://orcid.org/0000-0003-2169-2109, Schmoranzer, J., Prokop, S., Kessler, W., Kuhlmann, T., Möbius, W. ORCID: https://orcid.org/0000-0002-2902-7165, Nave, K.A. ORCID: https://orcid.org/0000-0001-8724-9666, Hornemann, T. ORCID: https://orcid.org/0000-0002-4218-1087, Becher, B. ORCID: https://orcid.org/0000-0002-1541-7867, Edgar, J.M. ORCID: https://orcid.org/0000-0002-3869-0962, Karaiskos, N. ORCID: https://orcid.org/0000-0001-7771-3947, Kocks, C. ORCID: https://orcid.org/0000-0003-1749-3334, Rajewsky, N. ORCID: https://orcid.org/0000-0002-4785-4332 and Heppner, F.L. ORCID: https://orcid.org/0000-0001-9816-8917
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| Abstract: | Neuroinflammation including interleukin (IL)-12/IL-23-signaling is central to Alzheimer’s disease (AD) pathology. Inhibition of p40, a subunit of IL-12/IL-23, attenuates pathology in AD-like mice; however, its signaling mechanism and expression pattern remained elusive. Here we show that IL-12 receptors are predominantly expressed in neurons and oligodendrocytes in AD-like APPPS1 mice and in patients with AD, whereas IL-23 receptor transcripts are barely detectable. Consistently, deletion of the IL-12 receptor in neuroectodermal cells ameliorated AD pathology in APPPS1 mice, whereas removal of IL-23 receptors had no effect. Genetic ablation of IL-12 signaling alone reverted the loss of mature oligodendrocytes, restored myelin homeostasis, rescued the amyloid-β-dependent reduction of parvalbumin-positive interneurons and restored phagocytosis-related changes in microglia of APPPS1 mice. Furthermore, IL-12 protein expression was increased in human AD brains compared to healthy age-matched controls, and human oligodendrocyte-like cells responded profoundly to IL-12 stimulation. We conclude that oligodendroglial and neuronal IL-12 signaling, but not IL-23 signaling, are key in orchestrating AD-related neuroimmune crosstalk and that IL-12 represents an attractive therapeutic target in AD. |
| Keywords: | Alzheimer Disease, Amyloid Beta-Peptides, Amyloid Beta-Protein Precursor, Animal Disease Models, Brain, Homeostasis, Interleukin Receptors, Interleukin-12, Interleukin-12 Receptors, Microglia, Neurons, Oligodendroglia, Signal Transduction, Transgenic Mice, Animals, Mice |
| Source: | Nature Aging |
| ISSN: | 2662-8465 |
| Publisher: | Springer Nature |
| Volume: | 5 |
| Number: | 4 |
| Page Range: | 622-641 |
| Date: | April 2025 |
| Official Publication: | https://doi.org/10.1038/s43587-025-00816-2 |
| PubMed: | View item in PubMed |
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